Abstract Stroke is one of the leading causes of adult disability in the United States, costing an estimated 33 billion dollars annually. Up to 30% of stroke patients experience cognitive decline in the first year after their stroke. There are no FDA approved drugs that can prevent post-stroke cognitive decline, a sub-category of vascular dementia, in part due to the mechanism(s) being poorly understood. Recently our lab published the first paper to show that an adaptive B-lymphocyte response to stroke can cause delayed cognitive dysfunction in mice, and that a similar adaptive immune response occurs in the brains of some human stroke patients that suffer from vascular dementia. This is the first evidence that in some people, post-stroke dementia may be caused by a B-lymphocyte response propagated by the stroke lesion. However, the precise mechanism by which B-lymphocytes mediate damage following stroke is still unknown. Discovering this mechanism is vital for developing treatments. Our proposed mechanism is that B-lymphocyte mediated cognitive impairment following stroke is T-cell dependent, requires a direct interaction between CD4+ T-follicular helper cells and B-lymphocytes, and is caused by the production of pathogenic central nervous system (CNS) specific autoantibodies. To test this hypothesis, I will generate transgenic mice with a conditional knockout of Bcl-6 in CD4+ cells. Bcl-6 is critical for the development of T-follicular helper cells, and so is critical for T-cell dependent B-lymphocyte activation. I will also inject into the brains of nave animals, antibodies isolated from mice that have undergone a mouse model of stroke, and I will perform modified sandwich ELISAs to determine if mice generate the same six CNS specific autoantibodies that have been found to occur in human stroke patients. The completion of these aims will lead to a greater understanding of the mechanisms by which B-lymphocytes can contribute to the development of cognitive decline in the weeks and months after stroke, which is necessary for the development of treatments that target B-lymphocyte responses to stroke.